Feedback loop and crosstalk in the mTORC1/2 signaling network

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Project Summary Deciphering feedback control and crosstalk between signaling molecules is critical to understand not only the mechanisms of cell growth/survival but also drug resistance in therapies. mTOR is regarded as one of the primary regulators of cellular fates by sensing and integrating cues from the cellular environment such as nutrients, energy, and stress. Thus, dysregulation of mTOR plays critical roles in the progression of diseases such as cancer, diabetes, and neurological disorders. Feedback signaling from mTOR has been of great interest as this suggests the major mechanisms by which cells adapt to the environmental stress and resist to drug treatment for their growth, proliferation, and survival. Many studies have focused on feedback signaling after partial mTOR complex 1 (mTORC1) inhibition by rapamycin, or knockout or knockdown of components in mTOR complexes. However, the feedback responses to mTOR kinase inhibition or suppression of both mTORC1/2 are not known. Because of the significant importance of mTOR feedback and crosstalk signaling, we have established a robust system to gain deep insight into the rewired signaling which determines cells’ survival and death strategies. Although it is generally believed that mTORC1/2 targeting will be a very promising tumor treatment, our studies using proteomics, metabolomics, glycomics, and biochemical/cellular methods reveal that dual mTORC1/2 inhibition leads to feedback activation of growth/survival signaling through integrin/ focal adhesion kinase/ insulin- like growth factor receptor signaling networks. Unexpectedly, mTORC1/2 suppression also mediates activation of Akt, one of the strongest survival kinase, by increasing phosphorylation at both its hydrophobic motif and turn motif. Considering the current paradigm that mTORC2 is the major kinase responsible for Akt phosphorylation at its hydrophobic motif, mTORC2-independent Akt activation in resistant cells highlights modification of the current paradigm that is extremely important for the successful clinical application of mTOR inhibitors. Also, surprisingly, the resistant cells increase migratory/invasive potential when mTORC1/2 is blocked. To elucidate our unexpected, but clinically pivotal observations, our specific aims are to determine the feedback activation mechanisms and crosstalk in mTOR signaling networks with focuses on 1) determining central molecules or pathway for mTORC2-independent Akt activation, 2) mechanisms by which cells induce cap-independent translation of survival factors and 3) mechanisms by which cells increase migratory and invasive potential following mTORC1/2 inhibition. Our proposed research is of therapeutic significance in that it will contribute to the deep understanding of why and how certain types of cells are sensitive, but other types are resistant to mTORC1/2 targeting, which will provide the basis for personalized medicine. Our study will also provide novel targets for which resistant tumor types can be treated with combinatorial drug treatments to be able to manage these tumors effectively. Thus, we expect that our study will provide a strong foundation to help develop successful mTORC1/2-targeted therapies.